It has been well established that T-cells play an important role in regulating immune response (F. Powrie and R. L. Coffman, Immunol. Today, 14, p. 270 (1993)). Indeed, activation of T-cells is often the initiating event in many inflammatory and autoimmune diseases. IL-2 is an autocrine growth factor which plays an essential role in the regulation of T-cell activation and proliferation. Furthermore, influx of extracellular calcium is necessary to achieve the elevated intracellular calcium levels required to initiate IL-2 gene transcription (W. Jy et al., BBA, 983, 153 (1989); S. C. Chung et al., Br. J. Pharmacol., 113, 861 (1994)). Inhibition of Ca.sup.+2 influx would therefore inhibit IL-2 production. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (T. A. Waldmann, Immunol. Today, 14, 270 (1993)). Accordingly, agents which inhibit Ca.sup.+2 influx and IL-2 production are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
Previously, others have attempted to interfere with the activity of IL-2 by using cytokine antagonists, monoclonal antibodies, toxins and other biologics which seek to prevent IL-2 from binding to its receptor (G. Mazur and I. Frydecka, Acta Haematol. Pol., 24(4), p. 307 (1993)). More recently, others have attempted to inhibit IL-2 production at the T cell level. However, to date, the reported compounds suffer from several disadvantages such as low potency, poor in vivo activity, cellular toxicity and poor oral bioavailability. Accordingly, a need exists for compounds that can effectively inhibit IL-2 production for preventing and treating immune disorders.
The compounds of this invention are 4-substituted .beta.-carbolines and .beta.-carboline analogs that are either unsubstituted or substituted with halo or C.sub.1 -C.sub.3 alkyl in the 1- and 3-positions. In general, a limited number of 4-substituted .beta.-carbolines are known in the art (see, for example, U.S. Pat. No. 5,010,077; Kuchova et al., Chem. Heterocycl. Compd., 6, 182 (1970); Haider and Plas, Tetrahedron, 46(10), 3641 (1990); Efremova et al., Chem. Heterocycl. Compd., 10, 1210 (1974); Fukada et al., Tetrahedron Lett., 26(18), 2139 (1985) and published PCT International Application No. WO 96/22989). Prior to this invention, however, there was no recognition or appreciation of the efficacy of 4-substituted .beta.-carbolines or .beta.-carboline analogs as inhibitors of Ca.sup.+2 influx and IL-2 production.